1. Field of Invention
This invention relates to an improved process of resolving a racemic mixture of 5-(2-(2-(2-ethoxyphenoxy) ethylamino) propyl)-2-methoxy benzene sulfonamide, commonly known as tamsulosin. This invention also relates to novel R and S isomers of 5-(2-(2-(2-ethoxyphenoxy)ethylamino)propyl)-2-methoxybenzene sulfonamide and their salts and processes for their preparation.
2. Description of Related Art
The compound tamsulosin (Structure I, below) is a new type of highly selective α-adrenoceptor antagonist, clinically useful for patients with urinary obstruction due to benign prostatic hyperplasia (BPH) and in cardiac insufficiency. The racemic compound and its applications are revealed in the European Patent No. 0034432, U.S. Pat. Nos. 4,373,106 and 4,868,216. Although there is a chiral center in the molecule (indicated by a star in Structure I), none of these patents disclose the existence of the optical isomers.

U.S. Pat. No. 4,772,475 discloses a controlled release formulation using racemic tamsulosin as the active ingredient. In all of these patents, only the tamsulosin hydrochloride salt has been considered for therapeutic applications.
U.S. Published Patent Application No. 2003/0109752 and WO 03/037850 disclose methods of obtaining solid racemic tamsulosin base in two polymorphic forms.
U.S. Pat. No. 4,703,063 discloses several “sulfamoyl-substituted phenethylamine derivatives” represented by a general formula in claim 1. Dependent claim 6 discloses racemic compounds of all of the analogs of claim 1. Similarly, claims 8 to 10 disclose all optically active compounds of claim 1. Claim 14 discloses the chemical name of tamsulosin, without mentioning the optical isomer. This racemic compound is described in example 20 only as its hydrochloride. As per example 20 and the scheme of its preparation in column 26 of the body of the patent, this compound was prepared by a non-stereospecific route resulting in a racemic compound only. There is neither a method of resolution nor a stereospecific synthetic route described for any compound claimed in the '063 patent.
U.S. Pat. No. 4,731,478 discloses the optical isomers of tamsulosin, but biological activity of only the (−) isomeric form is revealed. The two Examples, namely 33(a) and 33(b), describe a method of stereospecific synthesis of the optical isomers.
The stereospecific synthesis consists of condensing a chirally active intermediate amine, (R)(−)isomer as in Example 33(a) or (S)(+)isomer as in Example 33(b), with the achiral bromo intermediate to yield the corresponding chiral base and converting the same to its hydrochloride salt. Although the Example states that “crude crystals of (R)(−)-5-[2[2-(o-ethoxy phenoxy)ethylamino]-2-methylethyl]-2-methoxy benzene sulfonamide” were obtained, this base was not characterized further but converted to its salt, namely the hydrochloride. The hydrochloride was characterized only with its melting point, elemental analysis and optical rotation. Although the claims are exclusively for the optically active tamsulosin base (not the hydrochloride form) and specifically for (−) isomer of tamsulosin base (not the hydrochloride form), there is neither an Example nor a process described or suggested for the preparation of the pure “optically active” tamsulosin base. No characteristics of the “optically active” tamsulosin base are given anywhere in this patent or related patents by the same inventors. Even the specific optical rotation of the claimed (−)tamsulosin free base is not disclosed.
It is therefore believed that the applicants of the '478 patent failed to actually isolate and characterize the pure free bases of the two enantiomers of tamsulosin. No process for resolution of the racemic tamsulosin is shown or suggested in the '478 patent.
European Patent No. 02/57787 describes in Example 4 the preparation of (R)-tamsulosin by condensing the chiral intermediate R(−)5-(2-aminopropyl)-2-methoxy benzene sulfonamide, with the achiral intermediate 2-(2-ethoxyphenoxy)-ethyl bromide exactly as described in the U.S. Pat. No. 4,731,478. The same stereospecific synthetic process is also disclosed. However, there is no mention of any resolution process for the racemic compound.
U.S. Pat. No. 5,391,825 is similar to U.S. Pat. No. 4,731,478 in several aspects. Examples 33(a) and 33(b) in both patents reveal a method of preparing the optically active isomers as hydrochlorides by a synthesis using the appropriate chiral intermediate. However, the claims are limited to the achiral intermediate only. U.S. Pat. No. 5,447,958 claims the (R) tamsulosin as a compound and its application in pharmaceutical compositions. The method of its preparation as hydrochloride is given in Example 33(a) by synthesis using the chiral intermediate as in other U.S. patents cited earlier.
WO Patent No 03/035608 describes the same synthetic route to the (R) tamsulosin as a hydrochloride, however by improved conditions of reaction. In none of these patents is there shown a resolution process for obtaining the required (R) isomer from its racemic form. None of these patents discloses the characteristics of the free bases. It is thus believed that the pure R & S isomers were never isolated.
Although none of the patents mentioned above provide any biological data supporting the use of the (R) isomer in preference to the racemic form, the publication by Honda. K. and Nakagawa, C. in J. Pharm. Exp. Therap. 239, 512 (1986) suggests the advantage of the (R) isomer over the (S) isomer and the racemic form of tamsulosin.
U.S. Published Patent Application No. 2003/0109752 and its counterpart WO 03/037850 (PCT/NL02/00657) are applications disclosing means for resolving a racemic mixture of tamsulosin base. The racemic free base may be obtained directly by synthesis or the racemic salt may be converted to free racemic base followed by partial purification as camphor sulfonate addition salt, which is enriched in the ‘R’-isomer. The scheme is outlined in Chart I shown below:

The purity of the (R) isomer is low (68.7%) even after recrystallization. The applicants have developed another process, which results in an isomer having an enantiomeric purity of over 99.5%. The process is outlined in the Chart 2 given below. The starting material is purified racemic tamsulosin free base obtained by one of the methods as outlined in Chart 1 shown above.

The overall yield of the salt after four crystallizations was 47.4% based on the 76% purified free base. It is clear from the above that to obtain a purity of 99.5% for the (R) tamsulosin (−) camsylate salt itself, a very tedious process is required, which can then be converted to pure (R) tamsulosin by alkaline treatment.
According to WO 03/037850 at page 4, lines 3-4, prior to its publication, “no method was known as how to purify such an optically impure product (tamsulosin).” This patent application also failed to isolate free bases of the two enantiomers of tamsulosin and characterize them. It reveals only the solid form of racemic tamsulosin base, its application mainly for the resolution as described in the application.
Thus, there is a great need for developing a commercially viable, less tedious process of resolving racemic tamsulosin, which can be easily prepared by known methods, without resorting to chiral intermediates and stereospecific synthesis.
There is also a need for obtaining pure and well characterized R and S enantiomeric tamsulosin free bases. As the racemic mixture itself is being used in therapy since its launch, the presence of about 1% of the (S) isomer in the resolved and isolated (R) isomer does not adversely affect the improved activity of the (R) isomer. Moreover no adverse effects of the enriched (S) isomer are reported in literature. The pure isomers so obtained are excellent starting materials for conversion to optically pure salts other than the hydrochlorides.
All references cited herein are incorporated herein by reference in their entireties.